Staphylococcus aureus is an important pathogen and a major public health concern both in hospital and community settings. A central determinant of health or disease during staphylococcal infection is the host and bacterial antioxidant and redox systems. The phagocyte oxidative burst defends the host by generating reactive oxygen species (ROS) that are directly toxic to invading microorganisms, but ROS also serve as second messengers in key inflammatory signaling networks, and interfere with S. aureus virulence upregulation. S. aureus opposes this strategy by inactivating ROS using specific antioxidants. In this proposal, we hypothesize that the bacterial antioxidants function more than just a shield, and act to block host pro-inflammatory signaling through quenching of second messengers, and-inactivate ROS to minimize host interference with bacterial virulence. By implication, combined targeting of these bacterial enzymes could severely attenuate Staphylococcal virulence while providing a boost to the host immune defense. Our recent virulence studies have identified staphyloxanthin as an important antioxidant product upregulated during S. aureus pathogenesis (Liu et al. JEM 2005). Extending on this theme, our proposed research will investigate using molecular Koch's postulate the virulence and antioxidant functions of two additional S. aureus antioxidants, catalase and alkyl hydroperoxide reductase C (AhpC). In Specific Aim #1, we will define the contribution of catalase and AhpC to S. aureus virulence using molecular genetic methods. In Specific Aim #2, we will assess whether staphylococcal antioxidants modulate inflammatory signaling in phagocytes or prevent host manipulation of bacterial virulence. In Specific Aim #3 we will explore therapeutic approaches that target expression or function of these antioxidant products. Significance: The proposed research will address fundamental questions about S. aureus-host interaction, and uncover novel therapeutic approaches toward treatment of S. aureus diseases.